3VHK

Crystal structure of the VEGFR2 kinase domain in complex with a back pocket binder

Summary for 3VHK

• Entry DOI: 10.2210/pdb3vhk/pdb
• Descriptor: Vascular endothelial growth factor receptor 2, {3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}methanol, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: vegfr2, kinase domain, complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968
• Total number of polymer chains: 1
• Total formula weight: 42162.22

Authors

Iwata, H.,Oki, H.,Okada, K.,Takagi, T.,Tawada, M.,Miyazaki, Y.,Imamura, S.,Hori, A.,Hixon, M.S.,Kimura, H.,Miki, H. (deposition date: 2011-08-25, release date: 2012-09-05, Last modification date: 2024-03-20)

Primary citation

Iwata, H.,Oki, H.,Okada, K.,Takagi, T.,Tawada, M.,Miyazaki, Y.,Imamura, S.,Hori, A.,Lawson, J.D.,Hixon, M.S.,Kimura, H.,Miki, H.
A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.
ACS MED.CHEM.LETT., 3:342-346, 2012

PubMed Abstract: We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket-binding or hinge-binding). Next, fragments with the appropriate binding profile are assayed in combination with a known hinge-binding fragment and subsequently with a known back pocket-binding fragment. Confirmation of back pocket-binding by Yonetani-Theorell plot analysis progresses candidate fragments to crystallization trials. The method is exemplified by a fragment screening campaign against vascular endothelial growth factor receptor 2, and a novel back pocket-binding fragment is presented.

PubMed: 24900475
DOI: 10.1021/ml3000403

Experimental method

X-RAY DIFFRACTION (2.49 Å)